Methods of treating hepatitis E viral infection

ABSTRACT

Disclosed herein are methods of treating a hepatitis E viral infection comprising administering to a human subject in need thereof a therapeutically effective amount of the compound sofosbuvir, also known as (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate. Some methods further comprise concomitantly administering ribavirin to the subject. In some methods, the treatment is ribavirin-free. In some methods, the subject is immunocompromised. In some methods, the subject is pregnant.

CROSS REFERENCE

This application claims the benefit of U.S. Provisional Application62/345,188, filed on Jun. 3, 2016, the disclosure of which isincorporated herein by reference in its entirety.

FIELD

This application relates to various methods of treating Hepatitis Eviral (HEV) infection.

BACKGROUND

Hepatitis E virus (HEV) is believed to be the most common cause of acutehepatitis and jaundice in the world. Although HEV genotype 1 and 2infect only human beings, genotypes 3 and 4 are zoonotic viruses thatalso infect swine and other animal species. Acute hepatitis E usually isself-limited. However, HEV genotype 3 can persist in immunocompromisedpatients, especially organ transplant recipients, causing chronichepatitis, which may progress to cirrhosis and liver graft failure.Reduction of immunosuppressive therapy, ribavirin (RBV), or pegylatedinterferon-α have been used with varying success, allowing for viralclearance in up to 78% of patients. However, failure of RBV has beendescribed. Hence, safer and more effective treatment options are needed.

SUMMARY

One aspect provides for a method of treating a Hepatitis E viralinfection comprising administering to a human subject in need thereof atherapeutically effective amount of the compound of Formula (IA)

Some methods further comprise concomitantly administering ribavirin tothe subject. In some methods, the treatment is ribavirin-free. In somemethods, the subject is immunocompromised. In some methods, the subjectis pregnant.

Another aspect provides for a method of reducing the HEV RNA levels tolower than about 25 IU/mL in a human subject, comprising (1) identifyinga human subject with HEV RNA levels greater than about 1000 IU/mL, and(2) administering to that subject a therapeutically effective amount ofthe compound of Formula (IA).

Some methods further comprise concomitantly administering ribavirin tothe subject. In some methods, the concomitant administration of thecompound of Formula (IA) and ribavirin provides an additive orover-additive lowering of HEV RNA levels in the subject. In somemethods, the concomitant administration of the compound of Formula (IA)and ribavirin provides an over-additive lowering of HEV RNA levels inthe subject. In some methods, the no ribavirin is administered.

DETAILED DESCRIPTION

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The terms “optional” or “optionally” as used herein means that asubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “optional bond”means that the bond may or may not be present, and that the descriptionincludes single, double, or triple bonds.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R appears twice and is defined as“independently carbon or nitrogen”, both R's can be carbon, both R's canbe nitrogen, or one R′ can be carbon and the other nitrogen.

The term “alkenyl” refers to an unsubstituted hydrocarbon chain radicalhaving from 2 to 10 carbon atoms having one or two olefinic doublebonds, preferably one olefinic double bond.

The term “C_(2-N) alkenyl” refers to an alkenyl comprising 2 to N carbonatoms, where N is an integer having the following values: 3, 4, 5, 6, 7,8, 9, or 10. The term “C₂₋₁₀ alkenyl” refers to an alkenyl comprising 2to 10 carbon atoms. The term “C₂₋₄ alkenyl” refers to an alkenylcomprising 2 to 4 carbon atoms. Examples include, but are not limitedto, vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl).

The term “halogenated alkenyl” refers to an alkenyl comprising at leastone of F, Cl, Br, and I.

The term “alkyl” refers to an unbranched or branched chain, saturated,monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term“C_(1-M) alkyl” refers to an alkyl comprising 1 to M carbon atoms, whereM is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30. The term “C₁₋₄ alkyl” refers to an alkyl containing 1 to 4carbon atoms. The term “lower alkyl” denotes a straight or branchedchain hydrocarbon residue comprising 1 to 6 carbon atoms. “C₁₋₂₀ alkyl”as used herein refers to an alkyl comprising 1 to 20 carbon atoms.“C₁₋₁₀ alkyl” as used herein refers to an alkyl comprising 1 to 10carbons. Examples of alkyl groups include, but are not limited to, loweralkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl,t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. Theterm (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group isoptionally substituted by an aryl or a heteroaryl group respectively.

The term “cycloalkyl” refers to an unsubstituted or substitutedcarbocycle, in which the carbocycle contains 3 to 10 carbon atoms;preferably 3 to 8 carbon atoms; more preferably 3 to 6 carbon atoms(i.e., lower cycloalkyls). Examples of cycloalkyl groups include, butare not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term “cycloalkyl alkyl” refers to an additionally unsubstituted orsubstituted alkyl substituted by a lower cycloalkyl. Examples ofcycloalkyl alkyls include, but are not limited to, any one of methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl,neopentyl, hexyl, heptyl, and octyl that is substituted withcyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “cycloheteroalkyl” refers to an unsubstituted or substitutedheterocycle, in which the heterocycle contains 2 to 9 carbon atoms;preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms.Examples of cycloheteroalkyls include, but are not limited to,aziridin-2-yl, N—C₁₋₃-alkyl-aziridin-2-yl, azetidinyl,N—C₁₋₃-alkyl-azetidin-m′-yl, pyrrolidin-m′-yl,N—C₁₋₃-alkyl-pyrrolidin-m′-yl, piperidin-m′-yl, andN—C₁₋₃-alkyl-piperidin-m′-yl, where m′ is 2, 3, or 4 depending on thecycloheteroalkyl. Specific examples of N—C₁₋₃-alkyl-cycloheteroalkylsinclude, but are not limited to, N-methyl-aziridin-2-yl,N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-2-yl,N-methyl-piperidin-3-yl, and N-methyl-piperidin-4-yl. In the instance ofR⁴, the point of attachment between the cycloheteroalkyl ring carbon andthe oxygen occurs at any one of m′

The term “heterocycle” refers to an unsubstituted or substitutedheterocycle containing carbon, hydrogen, and at least one of N, O, andS, where the C and N can be trivalent or tetravalent, i.e., sp²- orsp³-hybridized. Examples of heterocycles include, but are not limitedto, aziridine, azetidine, pyrrolidine, piperidine, imidazole, oxazole,piperazine, etc. In the instance of piperazine, as related to R¹⁰ forNR′₂, the corresponding opposite nitrogen atom of the piperazinyl issubstituted by a lower alkyl represented by the following structure:

The term “halogenated alkyl” (or “haloalkyl”) refers to an unbranched orbranched chain alkyl comprising at least one of F, Cl, Br, and I. Theterm “C_(1-M) haloalkyl” refers to an alkyl comprising 1 to M carbonatoms that comprises at least one of F, Cl, Br, and I, where M is aninteger having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or30. “C₁₋₃ haloalkyl” refers to a haloalkyl comprising 1 to 3 carbons andat least one of F, Cl, Br, and I. The term “halogenated lower alkyl” (or“lower haloalkyl”) refers to a haloalkyl comprising 1 to 6 carbon atomsand at least one of F, Cl, Br, and I. Examples include, but are notlimited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl,difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl,trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl,1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl,2,2-dichloroethyl, 2,2-dibromomethyl, 2-2-diiodomethyl, 3-fluoropropyl,3-chloropropyl, 3-bromopropyl, 2,2,2-trifluoroethyl or1,1,2,2,2-pentafluoroethyl.

The term “alkynyl” refers to an unbranched or branched hydrocarbon chainradical having from 2 to 10 carbon atoms, preferably 2 to 5 carbonatoms, and having one triple bond. The term “C_(2-N) alkynyl” refers toan alkynyl comprising 2 to N carbon atoms, where N is an integer havingthe following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term “C C₂₋₄alkynyl” refers to an alkynyl comprising 2 to 4 carbon atoms. The term“C₂₋₁₀ alkynyl” refers to an alkynyl comprising 2 to 10 carbons.Examples include, but are limited to, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl or 3-butynyl.

The term “halogenated alkynyl” refers to an unbranched or branchedhydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2to 5 carbon atoms, and having one triple bond and at least one of F, Cl,Br, and I.

The term “cycloalkyl” refers to a saturated carbocyclic ring comprising3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl. The term “C₃₋₇ cycloalkyl” asused herein refers to a cycloalkyl comprising 3 to 7 carbons in thecarbocyclic ring.

The term “alkoxy” refers to an —O-alkyl group or an —O-cycloalkyl group,wherein alkyl and cycloalkyl are as defined above. Examples of —O-alkylgroups include, but are not limited to, methoxy, ethoxy, n-propyloxy,i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy. “Lower alkoxy” as usedherein denotes an alkoxy group with a “lower alkyl” group as previouslydefined. “C₁₋₁₀ alkoxy” refers to an —O-alkyl wherein alkyl is C₁₋₁₀.Examples of —O-cycloalkyl groups include, but are not limited to,—O-c-propyl, —O-c-butyl, —O-c-pentyl, and —O-c-hexyl.

The term “halogenated alkoxy” refers to an —O-alkyl group in which thealkyl group comprises at least one of F, Cl, Br, and I.

The term “halogenated lower alkoxy” refers to an —O-(lower alkyl) groupin which the lower alkyl group comprises at least one of F, Cl, Br, andI.

The term “amino acid” includes naturally occurring and synthetic α, β γor δ amino acids, and includes but is not limited to, amino acids foundin proteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In a preferred embodiment, the amino acid is inthe L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl,β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl orβ-histidinyl. When the term amino acid is used, it is considered to be aspecific and independent disclosure of each of the esters of α, β γ or δglycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tryptophan, proline, serine, threonine, cysteine,tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginineand histidine in the D and L-configurations.

The term “aminoacyl” includes N,N-unsubstituted, N,N-monosubstituted,and N,N-disubstituted derivatives of naturally occurring and syntheticα, β γ or δ amino acyls, where the amino acyls are derived from aminoacids. The amino-nitrogen can be substituted or unsubstituted. When theamino-nitrogen is substituted, the nitrogen is either mono- ordi-substituted, where the substituent bound to the amino-nitrogen is alower alkyl or an alkaryl. In the instance of its use for Y, theexpression “O(aminoacyl)” is used. It is understood that the C3′ carbonof the ribose is bound to the oxygen “O”, which is then bound to thecarbonyl carbon of the aminoacyl.

The terms “alkylamino” or “arylamino” refer to an amino group that hasone or two alkyl or aryl substituents, respectively.

The term “protected,” as used herein and unless otherwise defined,refers to a group that is added to an oxygen, nitrogen, or phosphorusatom to prevent its further reaction or for other purposes. A widevariety of oxygen and nitrogen protecting groups are known to thoseskilled in the art of organic synthesis. Non-limiting examples include:C(O)-alkyl, C(O)Ph, C(O)aryl, CH₃, CH₂-alkyl, CH₂-alkenyl, CH₂Ph,CH₂-aryl, CH₂O-alkyl, CH₂O-aryl, SO₂-alkyl, SO₂-aryl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

The term “aryl,” as used herein, and unless otherwise specified, refersto substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl,preferably the term aryl refers to substituted or unsubstituted phenyl.The aryl group can be substituted with one or more moieties selectedfrom among hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, and phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 3rd ed., John Wiley & Sons, 1999.

The terms “alkaryl” or “alkylaryl” refer to an alkyl group with an arylsubstituent, such as benzyl. The terms “aralkyl” or “arylalkyl” refer toan aryl group with an alkyl substituent.

The term “di(lower alkyl)amino-lower alkyl” refers to a lower alkylsubstituted by an amino group that is itself substituted by two loweralkyl groups. Examples include, but are not limited to, (CH₃)₂NCH₂,(CH₃)₂NCH₂CH₂, (CH₃)₂NCH₂CH₂CH₂, etc. The examples above show loweralkyls substituted at the terminus carbon atom with anN,N-dimethyl-amino substituent. These are intended as examples only andare not intended to limit the meaning of the term “di(loweralkyl)amino-lower alkyl” so as to require the same. It is contemplatedthat the lower alkyl chain can be substituted with an N,N-di(loweralkyl)-amino at any point along the chain, e.g., CH₃CH(N-(loweralkyl)₂)CH₂CH₂.

The term “halo,” as used herein, includes chloro, bromo, iodo andfluoro.

The term “acyl” refers to a substituent containing a carbonyl moiety anda non-carbonyl moiety. The carbonyl moiety contains a double-bondbetween the carbonyl carbon and a heteroatom, where the heteroatom isselected from among O, N and S. When the heteroatom is N, the N issubstituted by a lower alkyl. The non-carbonyl moiety is selected fromstraight, branched, and cyclic alkyl, which includes, but is not limitedto, a straight, branched, or cyclic C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or loweralkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl;aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyloptionally substituted with halogen (F, Cl, Br, I), hydroxyl, C₁ to C₄alkyl, or C₁ to C₄ alkoxy, sulfonate esters, such as alkyl or aralkylsulphonyl, including methanesulfonyl, the mono, di or triphosphateester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl(e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least onearyl group is present in the non-carbonyl moiety, it is preferred thatthe aryl group comprises a phenyl group.

The term “lower acyl” refers to an acyl group in which the non-carbonylmoiety is lower alkyl.

The term “purine” or “pyrimidine” base includes, but is not limited to,adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl,aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-allcylaminopurine, N⁶-thioallcyl purine, N²-alkylpurines,N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines,C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine,C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine,C⁵-iodopyrimidine, C⁶-Iodo-pyrimidine, C⁵—Br-vinyl pyrimidine,C⁶—Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine,N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, andpyrazolopyrimidinyl. Purine bases include, but are not limited to,guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.Functional oxygen and nitrogen groups on the base can be protected asnecessary or desired. Suitable protecting groups are well known to thoseskilled in the art, and include trimethylsilyl, dimethylhexylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups,and acyl groups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl.

The term “tautomerism” and “tautomers” have their accepted plainmeanings.

One aspect provides for methods for the treatment of a Hepatitis E viralinfection comprising administering to a subject in need thereof atherapeutically effective amount of a compound of Formula (I)

wherein

-   -   (a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or        aryl, which includes, but is not limited to, phenyl or naphthyl,        where phenyl or naphthyl are optionally substituted with at        least one of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        alkoxy, F, Cl, Br, I, nitro, cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂,        C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl, —SO₂N(R^(1′))₂, COR^(1″), and        —SO₂C₁₋₆ alkyl; (R^(1′) is independently hydrogen or alkyl,        which includes, but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl,        or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);    -   (b) R² is hydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R²        together are (CH₂)_(n) so as to form a cyclic ring that includes        the adjoining N and C atoms, C(O)CR^(3a)R^(3b)NHR¹, where n is 2        to 4 and R¹, R^(3a), and R^(3b);    -   (c) R^(3a) and R^(3b) are (i) independently selected from        hydrogen, C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆        hydroxyalkyl, —CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂,        (1H-indol-3-yl)methyl, (1H-imidazol-4-yl)methyl,        —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl, said aryl groups        optionally substituted with a group selected from hydroxyl,        C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii) R^(3a)        and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) together        are (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is        hydrogen and R^(3b) and R² together are (CH₂)_(n) so as to form        a cyclic ring that includes the adjoining N and C atoms (v)        R^(3b) is hydrogen and R^(3a) and R² together are (CH₂)_(n) so        as to form a cyclic ring that includes the adjoining N and C        atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, f is 2 to 5,        n is 2 to 4, and where R^(3′) is independently hydrogen or C₁₋₆        alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H and        R^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,        CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,        CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂,        —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃,        CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii) R^(3a) is        CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,        CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,        CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,        CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or        lower cycloalkyl and R^(3b) is H, where R^(3′) is independently        hydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀        alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″) is —OR′ or        —N(R^(3′))₂);    -   (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally        substituted with a lower alkyl, alkoxy, di(lower alkyl)-amino,        or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkyl alkyl,        cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,        such as, pyridinyl, substituted aryl, or substituted heteroaryl;    -   (e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl        lower alkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including        hydroxyl methyl (CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃,        CH₂N(CH₃)₂, alkyne (optionally substituted), or halogen,        including F, Cl, Br, or I, with the provisos that when X is OH,        base is cytosine and R⁶ is H, R⁵ cannot be N₃ and when X is OH,        R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;    -   (f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, Cl, Br, I, or CN;    -   (g) X is H, OH, F, Cl, Br, I, OMe, NH₂, CN, or N₃;    -   (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl,        N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄        alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀        haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄        alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄        alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl),        SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄        alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄        alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄        alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂,        N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl and vinyl are        optionally substituted by N₃, CN, one to three halogen (Cl, Br,        F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄        alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),        O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl),        S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄        alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl),        SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl),        OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl),        NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄        alkyl)₂, N(C₁₋₄ acyl)₂;    -   the base is a naturally occurring or modified purine or        pyrimidine base represented by the following structures:

-   -   wherein        -   Z is N or CR¹²;        -   R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F, Cl, Br, I,            OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,            halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower            alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenyl            of C₂-C₆, lower alkynyl of C₂-C₆ such as C≡CH, halogenated            (F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of            C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,            CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or            CH═CHCO₂R′,        -   wherein R′ is an optionally substituted alkyl, which            includes, but is not limited to, an optionally substituted            C₁₋₂₀ alkyl, an optionally substituted C₁₋₁₀ alkyl, an            optionally substituted lower alkyl; an optionally            substituted cycloalkyl; an optionally substituted alkynyl of            C₂-C₆, an optionally substituted lower alkenyl of C₂-C₆, or            optionally substituted acyl, which includes but is not            limited to C(O) alkyl, C(O)(C₁₋₂₀ alkyl), C(O)(C₁₋₁₀ alkyl),            or C(O)(lower alkyl) or alternatively, in the instance of            NR′₂, each R′ comprise at least one C atom that are joined            to form a heterocycle comprising at least two carbon atoms;            and        -   R¹² is H, halogen (including F, Cl, Br, I), OH, OR′, SH,            SR′, NH₂, NHR′, NR′₂, NO₂ lower alkyl of C₁-C₆, halogenated            (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,            halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower            alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkynyl            of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)            lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂,            CH═CHCO₂H, or CH═CHCO₂R′; with the proviso that when base is            represented by the structure c with R¹¹ being hydrogen, R¹²            is not a: (i) —C≡C—H, (ii) —C═CH₂, or (iii) —NO₂.

It is understood that the phosphorous atom is chiral and that it has acorresponding Cahn-Ingold-Prelog designation of “R” or “S” which havetheir accepted plain meanings. It is contemplated that compounds ofFormula I include compounds with both R and S stereochemistry at thephosphorous (“Rp” or “Sp”), including resolved Rp and Sp diastereomersas well as equal (racemic) and unequal (scalemic) mixtures thereof.

Another aspect provides for methods for the treatment of a Hepatitis Eviral infection comprising administering to a subject in need thereof atherapeutically effective amount of the compound of Formula (IA)

The compound of Formula (IA) is also known as sofosbuvir or by the IUPACname (S)-isopropyl2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate,and is described in, for example, U.S. Pat. No. 7,964,580. The compoundof Formula (IA) is a compound of Formula (I).

Concomitant administration refers to the administration of two or moreagents in any manner in which the pharmacological effects of both agentsare manifested in the subject at the same time. Although concomitantadministration includes simultaneous administration (e.g. via fixed-dosecombinations of two or more agents), it does not require that a singlepharmaceutical composition, the same type of formulation, the samedosage form, or even the same route of administration be used foradministration of the agents, or that the agents be administered at thesame time. For example, administration of a compound of Formula (I) andan additional antiviral agent may be concurrent, alternate, or anyvariation thereof, meaning that when the effective amounts of thecompound of Formula (I) and the additional antiviral agent areadministered during the same duration, the specific order ofadministration on a daily basis can be: the compound of Formula (I)followed by the additional antiviral agent, the compound of Formula (I)and the additional antiviral agent together, the additional antiviralagent followed by the compound of Formula (I), or any variation thereof.Additionally, it is contemplated that dosage frequencies of the compoundof Formula (I) and the additional antiviral agent may differ. As onenon-limiting example, the compound of Formula (I) may be administered QDwhile the additional antiviral agent is administered BID.

In certain embodiments, a compound of the present disclosure (e.g., acompound of Formula (I)), is formulated as a tablet, which may containone or more other compounds useful for treating HCV.

In certain embodiments, such tablets are suitable for once daily dosing.

In certain methods, the subject is a human.

In some methods, the subject is immunocompromised. In other methods, thesubject is not immunocompromised. In some methods, the subject ispregnant. In some methods, the subject is not pregnant.

Some methods further comprise concomitantly administering a firstantiviral agent and a second antiviral agent to the subject, wherein thefirst antiviral agent is a compound of Formula (I) and the secondantiviral agent is another therapeutic agent which may inhibit HEV viralreplication. Some methods further comprise concomitantly administeringribavirin to the subject (i.e. a method described above wherein thesecond antiviral agent is ribavirin). Some methods further compriseconcomitantly administering an interferon to the subject.

In some aspects, the concomitant administration of a first antiviralagent and a second antiviral agent provides an additive effect or anover-additive effect in lowering HEV RNA levels in a subject. As usedherein, the term “additive effect” refers to the combined effect of twoor more pharmaceutically active agents that is approximately equal tothe sum of the effect of each agent given alone, and the term“over-additive effect” refers to the combined effect of two or morepharmaceutically active agents that is greater than the sum of theeffect of each agent given alone. For example, in some methods, theconcomitant administration of a compound of Formula (I) and ribavirinprovides an over-additive lowering of HEV RNA levels in a subject. Forexample, in some methods, the concomitant administration of a compoundof Formula (IA) and ribavirin provides an over-additive lowering of HEVRNA levels in a subject.

Certain methods provide for prophylaxis of HEV infection. For example,certain methods disclosed herein involve administration prior an eventthat would expose the subject to HEV or that would otherwise increasethe subject's risk of acquiring HEV. Other methods involveadministration after such events. Other methods involve administrationboth prior to and after such events. Examples of events that couldincrease an individual's risk of acquiring HEV include, withoutlimitation, exposure to areas with poor sanitation; exposure to areaswith limited access to safe drinking water; exposure to animal feces;eating or exposure to meat and offal (including liver) of deer, boars,and pigs; eating or exposure to figatellu (a sausage prepared from rawpig liver); eating or exposure to shellfish; receiving a bloodtransfusion; exposure to blood.

Certain methods provide for reducing the HEV RNA levels in a subject tolower than about 25 IU/mL. For example, certain methods comprise (1)identifying a human subject with HEV RNA levels greater than about 1000IU/mL, and (2) administering to that subject a therapeutically effectiveamount of the compound of Formula (IA). Other methods provide formaintaining the HEV RNA levels in a subject to lower than about 25IU/mL. In certain of these methods, no ribavirin is administered. Incertain of these methods, no interferon is administered.

In certain methods, the effective amount of a compound of Formula (I)can be from about 100 mg to about 800 mg per day. For example, theeffective amount of a compound of Formula (I) can about 200 mg, about300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about800 mg per day. In some aspects, the effective amount of a compound ofFormula (I) is 400 mg per day. In some aspects, the effective amount ofthe compound of Formula (IA) is 400 mg per day.

In certain methods wherein ribavirin is administered, the amount ofribavirin is from about 100 mg to about 1400 mg per day. In certainaspects, the amount of ribavirin is from about 800 mg to about 1200 mgper day.

In certain methods, the duration of treatment is from about one week toabout 48 weeks. In certain methods, the duration of treatment is about24 weeks. In certain methods, the duration of treatment is about 12weeks. In certain methods, the duration of treatment is about 8 weeks.In certain methods, the duration of treatment is about 4 weeks.

EXAMPLES Example 1

A 55 year-old male human subject was identified as having AIDS, Kaposi'ssarcoma, non-Hodgkin's lymphoma, compensated cirrhosis, and a history ofalcoholism. An HEV RNA test of the subject was conducted, and the resultwas positive, at approximately 20,000 IU/mL. The subject was started onribavirin monotherapy, wherein ribavirin was administered to the subjectat 800 mg once per day. Despite ribavirin monotherapy treatment for overone year, the subject remained HEV-positive. The subject was thenstarted on a treatment wherein ribavirin administration was continued at800 mg per day and sofosbuvir was also administered at 400 mg per day.After four weeks of such treatment, the subject's HEV RNA levels werebelow the lower limit of detection of about 25 IU/mL.

We claim:
 1. A method of treating a Hepatitis E viral infectioncomprising administering to a human subject in need thereof atherapeutically effective amount of the compound of Formula (IA)

wherein the subject is pregnant.